The Wnt signaling pathway is a signal transduction pathway consisting of a group of proteins that pass signals from outside the cell through cell surface receptors to the inside of the cell. This leads to regulation of gene transcription e.g. embryonic development, cell fate specification, cell proliferation and cell migration. These processes are necessary for proper formation of important tissues such as heart, muscle and intestine. Mutations in the Wnt signaling pathway contibute to to a variety of disease, including different forms of cancer.
Canonical Wnt Signaling
In cells devoid of a Wnt signal, free cytoplasmic β-catenin is actively targeted for degradation (left panel). This is accomplished by two scaffolding proteins (Apc and Axin) that bind β-catenin. They reside in the so-called destruction complex. Two kinases (CK-1 and GSK3β) present in the same destruction complex sequentially phosphorylate a set of highly conserved Ser and Thr residues of β-catenin. Phospho-modified β -catenin becomes a substrate of the ubiquitin E3 ligase β-Trcp and is subsequently degraded in proteasomes. In the absence of Wnt signaling, Groucho proteins determine the nuclear DNA-binding proteins of the TCF/LEF family to act as transcriptional repressors of Wnt target genes.
Secreted Wnt proteins (19 family members) can induce signaling by interacting with Wnt receptor complexes consisting of a member of the Frizzled family (10 members) and the low-density lipid receptor family members LRP5 or LRP6. Wnt binding inactivates the destruction complex (right panel). As a direct consequence, β-catenin accumulates in the cytoplasm and nucleus and binds to members of the Tcf/Lef family, converting these into transcriptional activators. The Wnt signaling pathway is regulated extensively at the receptor–ligand level Secreted Frizzled-related proteins (Sfrp and Frzb) and Wnt inhibitory factor (WIF) can bind Wnt directly to prevent activation of receptors. Other Wnt antagonists, DKK1 and Wise, inhibit by binding to the LRP coreceptor.
Recently additional stem cell-specific regulators of canonical Wnt signaling (including Lgr4–6; the R-Spondins; and the E3 ligases RNF43 and ZNRF3) are discovered (not shown in the picture). Lgr5 was discovered as a Wnt target gene in adult intestinal crypts and colon. It was subsequently identified as a marker of multiple Wnt-driven adult stem cell types, including colon. Lgr5 and its homologs, Lgr4 and Lgr6, constitute the receptors for R-Spondins, potent Wnt signal enhancers and stem cell growth factors. The complex consisting of Lgr5/R-Spondin acts by neutralizing two transmembrane E3 ligases RNF43 and ZNRF3, that remove Wnt receptors from the stem cell surface. RNF43/ZNRF3 are themselves encoded by Wnt target genes and constitute a negative Wnt feedback loop. Thus, adult stem cells are regulated by an intricate interplay of potent Wnt stimulators and inhibitors.
Reprinted from De Lau, W., Peng, W.C., Gros, P., and Clevers, H. (2014). The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28, 305–316.